Pharmacologically active catechol derivatives

ABSTRACT

New catechol derivatives and pharmaceutically acceptable salts and esters thereof useful as pharmaceutical antioxidants are disclosed. Cellular damage by oxygen derived radicals is a significant factor in heart disease, rheumatoid arthritis, cancer, inflammatory disease, transplant rejection reactions and ischemia.

This application is a divisional of application Ser. No. 07/949,477, filed Oct. 23, 1992 now U.S. Pat. No. 5,362,733.

The invention relates to new catechol derivatives and pharmaceutically acceptable salts and esters thereof which are useful as medicinal antioxidants. The invention also relates to pharmaceutical compositions containing said compounds and to the method of the preparation of the same.

Medicinal antioxidants are compounds that may be used for the prevention or treatment of tissue damage induced by lipid peroxidation. It is generally believed that cellular damage by oxygen derived radicals, especially those associated with lipid peroxidation, is a significant factor in heart diseases, rheumatoid arthritis, cancer, certain inflammatory diseases, rejection reactions in transplantation, ischemia and even in the aging process.

EP-A-343643 describes pharmaceutical compositions comprising the compounds of formula ##STR1## wherein Ar is (i) phenyl unsubstituted, (ii) phenyl substituted by from one to three of lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, NR₁₀ R₁₁, wherein R₁₀ and R₁₁ are independently hydrogen or lower alkyl, NO₂, mercapto, or lower alkylthio, (iii) naphthyl; (iv) benzofuranyl, (v) benzothiophenyl, (vi) 2- or 3-thienyl, (vii) 2- or 3-indolyl, (viii) 2- or 3-furanyl, or (ix) 2-, 3-, or 4-pyridyl.

Y and Y₁ is oxygen or sulfur; X is sulfur, oxygen, NH or NCH₃ and X₁ is NH or NCH₃ and pharmaceutically acceptable salts thereof which are stated to be 5-lipoxygenase and/or cyclooxygenase inhibitors. Japanese patent application No. 1052765, which has been referred to in Chemical Abstracts (CA 111(17)153788y) discloses thiazolidinone derivatives which are useful as aldose reductase inhibitors. Gupta et al. in Eur. J. Med. Chem.--Chim. Ther., 17 (5), 448-52, 1982 and Srivastava et al. in Pharmazie, 36(4), 252-3, 1981 disclose 2-thioxo-4,6-pyrimidinedione compounds having anticonvulsant activity. Sohda et al. in Chem. Pharm. Bull., 31(2), 560-9, 1983 discloses 2,4-thioxolidione derivatives having antiulcer activity.

The compounds of the present invention may be represented by the formula I ##STR2## wherein R₁ is an electronegative substituent such as nitro, halogeno or cyano group and R₂ is a group selected from ##STR3## wherein R is hydrogen, or an alkyl, cycloalkyl, aralkyl or aryl group, wherein X₁, X₂, Y and Z are independently oxygen, sulfur or NR wherein R may be as defined above. In one embodiment, R₂ is a group containing a five membered heterocyclic ring which is of formula ##STR4## in which X₁ and X₂ are both NR, wherein R is hydrogen or alkyl, Y is oxygen or sulfur and Z is oxygen or sulfur. Preferred ring systems include 2-thioxoimidazolidin-5-ones and 2,5-imidazolidin-5-ones. Examples of such compounds include 4-[(3,4-dihydroxy-5-nitrophenyl) methylidene]-2-thioxoimidazolidin-5-one; 4-[(3,4-dihydroxy-5-chlorophenyl)-methylidene]-2-thioxoimidazolidin-5 -one; 4-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione and 4-[(3,4-dihydroxy-5-cyanophenyl)methylidene]-2-thioxoimidazolidin-5-one.

In another embodiment R₂ is the group ##STR5## in which X₁, Y, and Z are independently oxygen or sulfur and X₂ is NR, in which R is hydrogen or alkyl. Preferred ring systems include 2-thioxothiazolidin-4-ones; 3-methyl-2-thioxothiazolidin-4-ones; thiazolidin-2,4-diones; 4-thioxo-2-oxazolidinones and 4-thioxithiazolidin-2-ones. Specific examples are 5-[(3,4-dihydroxy-5-nitrophenyl)-methylidene]-2-thioxothiazolidin-4-one; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-3-methyl-2-thioxothiazolidin-4-one; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione; 5-[(3,4 -dihydroxy-5-chlorophenyl)methylidene]-thiazolidin-2,4-dione; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-4-thioxo-2-oxazolidinone; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-4-thioxo-thiazolidin-2-one and 5-[(3,4-dihydroxy-5-cyanophenyl)methylidene]-2-thioxothiazolidin-4-one.

In another embodiment R₂ is the group ##STR6## in which X₁ and Z are independently oxygen or sulfur and Y and X₂ are NR, wherein R is hydrogen. Preferred ring system is 2-aminothiazolidin-4-one. A specific example is 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2-amino-thiazolidin-4-one.

In another embodiment R₂ is a group containing a six-membered heterocyclic ring which is of formula: ##STR7## wherein Y is oxygen or sulfur, X₁ is NR, wherein R is hydrogen or alkyl. Preferably Y is oxygen. Preferred ring systems include pyrimidine-2,4-6-trione. Examples of such compounds include 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2,4,6 (1H,3H,5H) -pyrimidinetrione and 5-[(3,4-dihydroxy-5-nitrophenyl)methyl]-(1H,3H,5H) -pyrimidine-2,4,6-trione.

The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain groups, preferably of 1 to 8 atoms, most preferably of 1 to 4 carbon atoms.

The term "aryl" as employed herein refers to a monocyclic or bicyclic group containing 6 or 10 carbon atoms in the ring portion. A specific example is phenyl.

The term "acyl" as employed herein refers to alkylcarbonyl group, the alkyl group being as defined above.

The term "aroyl" refers to an arylcarbonyl group, the aryl group being defined above.

The term "cycloalkyl" as employed herein refers to saturated cyclic hydrocarbon groups having preferably 5 to 7 carbon atoms.

The term "halogeno" as employed herein refers to fluoro, chloro, bromo or iodo substituent. Especially preferred is chloro.

If R is hydrogen the compounds of the present invention may exist also in the corresponding tautomeric forms depending on the pH of the solution

Thus, when R₂ is a five-membered ring, when X₁ is NR wherein R is hydrogen the tautomeric forms of the compounds according to formula Ia are ##STR8## and the tautomers, when X₂ is NR wherein R is hydrogen are ##STR9##

The tautomeric forms for the compounds wherein R₂ is a six membered ring are respectively ##STR10##

The present invention also relates to the method for the preparation of compounds of formula I. The present invention provides a process for the preparation of compounds of formula I, in which process an aldehyde of formula II ##STR11## wherein R₁ is as defined above, is condensed in a base or acid catalyzed reaction with compounds of either formulas III or IV having an active methylene group ##STR12## wherein X₁, X₂, Y and Z are as defined above, to give a compound Ia according to the present invention, whereafter the carbon-carbon double bond in Ia may be reduced to give the compound Ib according to the invention.

The invention also relates to pharmaceutically acceptable salts and esters of the present compounds. Generally, the esters which hydrolyze readily in physiological circumstances are those attached to the phenolic hydroxyl groups in compounds according to formula I. Either one of the hydroxylic groups or both of them may be esterified and on hydrolyzing the ester-forming group or groups are cleaved away and the active compound is liberated. Preferred esters are acyl or aroyl derivatives.

Salts of the compounds, when applicable, may be prepared by known methods. Physiologically acceptable salts are useful as active medicaments. However, sodium, potassium, ammonium, calcium and magnesium salts are preferred.

The effective dose of the compound varies considerably depending on whether the compounds are given for prophylaxis or for treatment, the severity of the condition to be treated, and the route of administration. The effective dose for human beings is likely to be from about 1 to 1000 mg per day.

The compounds used in this invention are formulated into dosage forms using the principles which are known to the man having average skill in the art. The compounds according to this invention are given to a patient as such or in combination with suitable pharmaceutical material in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions whereby the content of the active compound is in the formulation from 1 to 100 weight %.

Choosing the auxiliary ingredients for the formulation is routine for those of ordinary skill in the art. It is evident that suitable solvents, gel forming ingredients, dispersion forming ingredients, colors etc are used in a normal way.

The compositions may be administered enterally or parenterally.

TEST RESULTS Radical Trapping Capacity of Compounds

The tested compounds were subjected to controlled peroxidation by peroxylradicals originating from the thermal decomposition of 2,2'-azobis-(2-amidinopropane)×HCl at 37° C. The rate of radical formation was followed by luminol enhanced chemiluminescence (CL). From the duration of CL and from the fact that the phenolic antioxidant vitamin E analogue TROLOX® traps two radicals (Barclay, L. et al., J. Am. Chem. Soc. 106: 2479-2481, 1984) the stochiometric factors were calculated. The results are presented in Table

                  TABLE 1                                                          ______________________________________                                         The binding of peroxyl radicals by various test compounds                      Compound     Stoichiometric factor                                             ______________________________________                                         1            7.1                                                               2            5.6                                                               3            4.7                                                               4            4.4                                                               5            4.2                                                               6            4.0                                                               7            4.0                                                               TROLOX       2.0                                                               Ascorbic acid                                                                               0.7                                                               ______________________________________                                          1 4[(3,4dihydroxy-5-chlorophenyl)methylidene2-thioxoimidazolidin-5-one         2 5[(3,4dihydroxy-5-cyanophenyl)methylidene2-thiozothiazolidin-4-one           3 4[(3,4dihydroxy-5-nitrophenyl)methylidene2,5-imidazolindione                 4 5[(3,4dihydroxy-5-nitrophenyl)methylidene2-thioxothiazolidin-4-one           5 4[(3,4dihydroxy-5-nitrophenyl)methylidene2-thioxoimidazolidin-5-one          6 5[(3,4dihydroxy-5-nitrophenyl)methylidene2,4,6                               (1H,3H,5H)pyrimidinetrione                                                     7 4[(3,4dihydroxy-5-cyanophenyl)methylidene2-thioxoimidazolidin-5-one    

The following examples illustrate the preparation of the compounds according to the invention.

EXAMPLE 1 4-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2-thioxoimidazolidin-5 -one

A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 100° C. The crystals were filtered and washed with 2-propanol. Yield 5.0 g (71%), mp>350° C. (decom.).

EXAMPLE 2 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2-thioxothiazolidin-4-one

A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100° C. After cooling the crystals were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp >350° C. (decomp.).

EXAMPLE 3 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione

A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80° C. The crystals were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295°-298° C.

EXAMPLE 4 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2-aminothiazolidin-4-one

A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 24 h at 100° C. The product was filtered and washed with ethanol. Yield 1.2 g (86%), mp 250° C. (decomp.).

EXAMPLE 5 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-4-thioxothiazolidin-2-one

A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidin-2-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 1.14 g (76.5%), mp >350° C. (decomp.).

EXAMPLE 6 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-3-methyl-2-thioxothiazolidin-4-one

A solution containing 0.74 g (0.005 mol) of 3-methyl-2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274°-276° C.

EXAMPLE 7 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2,4,6(1H,3H,5H)-pyrimidinetrione.

To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room temperature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%) , mp 269°-272° C.

EXAMPLE 8 4-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione

A solution containing 0.65 g of hydantoin, 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2-propanol. Yield 0.56 g (42%), mp >350° C.

EXAMPLE 9 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-4-thioxo-2-oxazolidinone

A solution containing 0.25 g of 4-thioxo-2-oxazolone 0.38 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid was heated overnight at 100° C. The product was filtered and washed with actic acid. Yield 0.05 g, mp 245° C.

EXAMPLE 10 4-[(3,4-Dihydroxy-5-cyanophenyl)methylidene]-2-thioxo-imidazolidin-5-one

A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 0.51 g, mp 210°-213° C.

EXAMPLE 11

5-[(3,4-Dihydroxy-5-cyanophenyl)methylidene]-2-thioxothiazolidin-4-one

A solution containing 0.61 g of rhodanine, 0.72 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.35 g, mp >350° C.

EXAMPLE 12 4-[(3,4-Dihydroxy-5-chlorophenyl)methylidene]-2-thioxoimidazolidin-5-one

A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 1.0 g, mp 303°-304° C.

EXAMPLE 13 5-[(3,4-Dihydroxy-5-chlorophenyl)methylidene]-thiazolidin-2,4-dione

A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated for five hours at 100° C. Yield 1.9 g (70%), mp 299°-301° C.

EXAMPLE 14 5-[(3,4-Dihydroxy-5-nitrophenyl)methyl]-(1H,3H,5H)pyrimidine-2,4,6-trione

To a suspension of 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-(1H,3H,5H) pyrimidine-2,4,6-trione (Example 7) (1 g) in water (30 ml) a solution of sodiumborohydride (2 g) in water (10 ml ) was gradually added. The solution was stirred for 15 min at room temperature and acidified with 1N hydrochloric acid. The product was filtered and washed with water. Yield 0.7 g, mp 263°-6° C. 

We claim:
 1. A compound according to formula I ##STR13## wherein R₁ is nitro, halogeno or cyano group and R₂ is a group selected from ##STR14## wherein X₂ is NR, in which R is hydrogen or C₁₋₈ alkyl and a) X₁ is S, Y is S and Z is O,b) X₁ is S, Y is O and Z is S, or c) X₁ and Z are independently oxygen or sulfur and Y is NR and R is hydrogen, or a pharmaceutically acceptable salt or ester thereof.
 2. The compound as claimed in claim 1, wherein R₁ is cyano.
 3. The compound as claimed in claim 1, wherein R₁ is nitro.
 4. The compound as claimed in claim 1, wherein R₁ is halogeno.
 5. The compound as claimed in claim 1, wherein the compound of formula I, R₂ is a group according to formula Ia, ##STR15## wherein X₂ is NR, in which R is hydrogen or C₁₋₈ alkyl and a) X₁ is S, Y is S and Z is O, orb) X₁ is S, Y is O and Z is S.
 6. The compound as claimed in claim 5, wherein R₁ is cyano.
 7. The compound as claimed in claim 5, wherein R₁ is nitro.
 8. The compound as claimed in claim 5, wherein R₁ is halogeno.
 9. The compound as claimed in claim 8, which is selected from the group consisting of:5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2-thioxothiazolidin-4-one; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-3-methyl-2-thioxothiazolidin-4-one; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione; 5-[(3,4-dihydroxy-5-chlorophenyl)methylidene]-thiazolidin-2,4-dione; 5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-4-thioxothiazolidin-2-one; 5-[(3,4-dihydroxy-5-cyanophenyl)methylidene]-2-thioxothiazolidin-4--one; and the pharmaceutically acceptable salts and esters thereof.
 10. The compound as claimed in claim 9, which is 5-[(3,4-dihydroxy-5-cyanophenyl)methylidene]-2-thioxothiazolidin-4-one or a pharmaceutically acceptable salt or ester thereof.
 11. The compound as claimed in claim 1, wherein in the compound of formula I, R₂ is a group according to formula Ia, ##STR16## in which X₁ and Z are independently oxygen or sulfur and Y and X₂ are NR, wherein R is hydrogen.
 12. A pharmaceutical composition for use in the prevention or treatment of tissue damage induced by lipid peroxidation, said composition comprising an effective antioxidant amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent therefor.
 13. A method for the prevention or treatment of tissue damage induced by lipid peroxidation in an animal in need for such prevention or treatment, said method comprising administering to said animal an effective antioxidant amount of a compound as claimed in claim
 1. 14. A method as claimed in claim 13, wherein the tissue damage is associated with heart disease, rheumatoid arthritis, cancer, an inflammatory disease, transplantation rejection reaction, or ischemia.
 15. 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2-amino-thiazolidin-4-one or a pharmaceutically acceptable salt or ester thereof. 